Alzheimer's Disease
Alzheimer's disease (AD) is a progressive disease known generally as senile dementia. Broadly speaking the disease falls into two categories, namely late onset and early onset. Late onset, which occurs in old age (65+years), may be caused by the natural atrophy of the brain occurring at a faster rate and to a more severe degree than normal. Early onset AD is much more infrequent but shows a pathologically identical dementia with brain atrophy which develops well before the senile period, i.e., between the ages of 35 and 60.
Alzheimer's disease is characterized by the presence of numerous amyloid plaques and neurofibrillary tangles (highly insoluble protein aggregates) present in the brains of AD patients, particularly in those regions involved with memory and cognition. While in the past there was significant scientific debate over whether the plaques and tangles are a cause or are merely the result of AD, recent discoveries indicate that amyloid plaque is a causative precursor or factor. In particular, it has been discovered that the overproduction of .beta.-amyloid peptide ("A.beta."), a major constituent of the amyloid plaque, can result from mutations in the gene encoding amyloid precursor protein, a protein which when normally processed will not produce the A.beta. peptide.
One hypothesis regarding the pathogenesis of the disease is that deposition of A.beta. peptide, which is the major macromolecular component of amyloid plaques, is the causative agent of the characteristic AD pathological changes leading to formation of neurofibrillary tangles, neuronal cell loss, vascular damage, and, ultimately, dementia (Hardy and Higgins (1992) Science 256: 184). Amyloid precursor protein (APP) is encoded by a single gene in humans. RNA transcripts of the APP gene are alternatively spliced to encode several APP protein isoforms; the predominant APP isoform in brain lacks a serine protease inhibitor domain that is present in other tissues. A.beta. is a proteolytic cleavage product arising from the carboxy region of various APP isoforms, including the predominant APP isoform in the brain (U.S. Pat. No. 4,666,829; Glenner and Wong (1984) Biochem. Biophys. Res. Commun. 120: 1131; Kitaguchi et al. (1988) Nature 331: 530; Ponte et al., ibid., p.525; R. E. Tanzi, ibid., p.528; Kang and Muller-Hill (1990) Biochem. Biophys. Res. Commun. 166: 1192; Yoshioka et al. (1991) Biochem. Biophys. Res. Commun. 178: 1141; Johnson et al. (1990) Science 248: 854; Neve et al. (1990) Neuron 5: 329). The accumulation of extracellular A.beta. results in insoluble amyloid deposits and may be neurotoxic, leading to neuronal death and neurofibrillary tangle formation.
Moreover, A.beta. peptide appears to be toxic to brain neurons, and neuronal cell death is associated with the disease (Schubert et al. (1995) Proc. Natl. Acad. Sci. (USA) 92: 1989; Lorenzo and Yankner (1994) Proc. Natl. Acad. Sci. (USA) 91: 12243; Yankner et al. (1990) Science 250: 279; Kowall et al. (1991) Proc. Natl. Acad. Sci. (USA) 88: 7247; and Pike et al. (1993) J. Neurosci. 13: 1676). Mattson et al. (1992) J. Neurosci. 12: 376 and Mattson et al. (1993) Trends in Neuroscience 16: 409, report that A.beta. and fragments thereof can destabilize calcium (Ca.sup.+2) homeostasis in cultured human cortical neurons, and can render the neurons more susceptible to calcium ionophore-induced neurotoxicity. Meda et al. (1995) Nature 374: 647 report that A.beta. and IFN-.gamma. activates cultured microglial cells, leading to neuronal cell injury in co-cultured neurons. Both Meda et al. (1995) op.cit and Schubert et al. (1995) op.cit report the likely involvement of reactive free radical species, such as reactive nitrogen intermediates and reactive oxygen species.
Reports show that soluble A.beta. peptide is produced by healthy neuronal cells in culture media (Haass et al. (1992) Nature 359: 322) and is present in human and animal cerebrospinal fluid (Seubert et al. (1992) Nature 359: 325). Thus, the mere presence of soluble A.beta. peptide may not be sufficient for explaining the onset and progression of AD. However, aggregation and formation of insoluble complexes of A.beta. have been implicated as having enhanced neurotoxicity to cultured neuronal cells.
To date, the exact molecular mechanisms which result in the characteristic pathology and neuronal deficits of Alzheimer's disease have not been described in the art. The development of experimental models of Alzheimer's disease that can be used to define further the underlying biochemical events involved in AD pathogenesis would be highly desirable. Such models could presumably be employed, in one application, to screen for agents that alter the degenerative course of Alzheimer's disease. For example, a model system of the biochemical events which contribute to the pathology of Alzheimer's disease could be used to screen for drugs or therapeutic regimens that reverse, arrest, or slow the pathogenesis and progression of AD. Presumably, such models could be employed to develop pharmaceuticals that are effective in preventing, arresting, or reversing AD.
Currently, there are no human pharmaceuticals which are known to be effective in inhibiting the development or progression of the degenerative CNS neuropathology of Alzheimer's Disease. U.S. Pat. No. 5,192,753 report that certain non-steroidal anti-inflammatory drugs useful in treating rheumatoid arthritis (e.g., indomethacin) are allegedly useful in reducing symptomatic progression in a selected group of five AD patients, but no effects on neuropathological progression were noted and the sample size and experimental methodology employed were insufficient to conclusively demonstrate efficacy. U.S. Pat. No. 5,137,873 disclose the use of tachykinin agonists to treat AD, although this approach has not proven successful in producing substantial amelioration of the progression of AD, and significantly more effective therapeutic agents are desired in the art.
There is a need in the art for new compounds having therapeutic use to treat or prevent Alzheimer's Disease and A.beta.-related neurodegenerative diseases which have similar pathogenic mechanisms. The present invention provides such new compounds, compositions and methods of treatment.